RESUMEN
The COVID-19 pandemic initiated a worldwide race toward the development of treatments and vaccines. Small animal models included the Syrian golden hamster and the K18-hACE2 mice infected with SARS-CoV-2 to display a disease state with some aspects of human COVID-19. A group activity of animals in their home cage continuously monitored by the HCMS100 (Home cage Monitoring System 100) was used as a sensitive marker of disease, successfully detecting morbidity symptoms of SARS-CoV-2 infection in hamsters and in K18-hACE2 mice. COVID-19 convalescent hamsters rechallenged with SARS-CoV-2 exhibited minor reduction in group activity compared to naive hamsters. To evaluate the rVSV-ΔG-spike vaccination efficacy against SARS-CoV-2, we used the HCMS100 to monitor the group activity of hamsters in their home cage. A single-dose rVSV-ΔG-spike vaccination of the immunized group showed a faster recovery than the nonimmunized infected hamsters, substantiating the efficacy of rVSV-ΔG-spike vaccine. HCMS100 offers nonintrusive, hands-free monitoring of a number of home cages of hamsters or mice modeling COVID-19.
RESUMEN
The development of refractory status epilepticus (SE) induced by sarin intoxication presents a therapeutic challenge. In our current research we evaluate the efficacy of a delayed combined triple treatment in ending the abnormal epileptiform seizure activity (ESA) and the ensuing of long-term neuronal insult. SE was induced in male Sprague-Dawley rats by exposure to 1.2LD50 sarin insufficiently treated by atropine and TMB4 (TA) 1 min later. Triple treatment of ketamine, midazolam and valproic acid was administered 30 min or 1 h post exposure and was compared to a delayed single treatment with midazolam alone. Toxicity and electrocorticogram activity were monitored during the first week and behavioral evaluation performed 3 weeks post exposure followed by brain biochemical and immunohistopathological analyses. The addition of both single and triple treatments reduced mortality and enhanced weight recovery compared to the TA-only treated group. The triple treatment also significantly minimized the duration of the ESA, reduced the sarin-induced increase in the neuroinflammatory marker PGE2, the brain damage marker TSPO, decreased the gliosis, astrocytosis and neuronal damage compared to the TA+ midazolam or only TA treated groups. Finally, the triple treatment eliminated the sarin exposed increased open field activity, as well as impairing recognition memory as seen in the other experimental groups. The delayed triple treatment may serve as an efficient therapy, which prevents brain insult propagation following sarin-induced refractory SE, even if treatment is postponed for up to 1 h.
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Anticonvulsivantes/administración & dosificación , Encéfalo/efectos de los fármacos , Ketamina/administración & dosificación , Midazolam/administración & dosificación , Sarín , Estado Epiléptico/tratamiento farmacológico , Ácido Valproico/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Proteínas Portadoras/metabolismo , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Esquema de Medicación , Quimioterapia Combinada , Inyecciones Intramusculares , Inyecciones Intraperitoneales , Masculino , Prueba de Campo Abierto/efectos de los fármacos , Ratas Sprague-Dawley , Receptores de GABA-A/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Estado Epiléptico/inducido químicamente , Estado Epiléptico/patología , Estado Epiléptico/fisiopatología , Factores de TiempoRESUMEN
Large numbers of rodents are often used in the study of disease progression and in the evaluation of its potential treatments. To avoid subjective observation and to minimize home cage interference, we developed a computerized home cage monitoring system (HCMS100) based on a standard cage rack adapted with a single laser beam and a detector mounted on each cage, enabling to monitor mice movements based on laser beam interruptions. This retrofit system provided continuous and uninterrupted monitoring of spontaneous movement of a group of mice in a home cage. Validity was evaluated using disease state induced by LPS modelling bacterial infection and by influenza virus. RESULTS: Spontaneous activity of different number of mice (2-8) per cage showed the expected circadian rhythm with increased activity during the night, and its extent dependent on the number of mice in the cage. Females and males show similar circadian rhythm. Intranasal LPS administration and pulmonary infection with live influenza virus resulted in major reduction of mice activity along disease progression. Increase in activity over time was a good indicator of the recovery process from both LPS exposure and the flu infection. CONCLUSIONS: HCMS100 was shown to be a reliable, inexpensive, easy to use system that requires no changes in the common housing of various experimental animals (mice, hamsters, rats etc.). With minimal intervention, HCMS100 provides a continuous record of group activity with clear pattern of circadian rhythm, allowing long term recording of home cage activity even in restricted access environments.
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Progresión de la Enfermedad , Vivienda para Animales , Lipopolisacáridos/toxicidad , Infecciones por Orthomyxoviridae/fisiopatología , Orthomyxoviridae , Recuperación de la Función/fisiología , Animales , Ritmo Circadiano/fisiología , Femenino , Vivienda para Animales/tendencias , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Infecciones por Orthomyxoviridae/psicología , Recuperación de la Función/efectos de los fármacosRESUMEN
BACKGROUND: Sarin is an irreversible organophosphate cholinesterase inhibitor. Following toxic signs, an extensive long-term brain damage is often reported. Thus, we evaluated the efficacy of a novel anticonvulsant drug retigabine, a modulator of neuronal voltage gated K+ channels, as a neuroprotective agent following sarin exposure. METHODS: Rats were exposed to 1 LD50 or 1.2 LD50 sarin and treated at onset of convulsions with retigabine (5 mg/kg, i.p.) alone or in combination with 5 mg/kg atropine and 7.5 mg/kg TMB-4 (TA) respectively. Brain biochemical and immunohistopathological analyses were processed 24 h and 1 week following 1 LD50 sarin exposure and at 4 weeks following exposure to 1.2 LD50 sarin. EEG activity in freely moving rats was also monitored by telemetry during the first week following exposure to 1.2 LD50 and behavior in the Open Field was evaluated 3 weeks post exposure. RESULTS: Treatment with retigabine following 1 LD50 sarin exposure or in combination with TA following 1.2 LD50 exposure significantly reduced mortality rate compared to the non-treated groups. In both experiments, the retigabine treatment significantly reduced gliosis, astrocytosis and brain damage as measured by translocator protein (TSPO). Following sarin exposure the combined treatment (retigabine+ TA) significantly minimized epileptiform seizure activity. Finally, in the Open Field behavioral test the non-treated sarin group showed an increased mobility which was reversed by the combined treatment. CONCLUSIONS: The M current modulator retigabine has been shown to be an effective adjunct therapy following OP induced convulsion, minimizing epileptiform seizure activity and attenuating the ensuing brain damage.
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Anticonvulsivantes/administración & dosificación , Encefalopatías/inducido químicamente , Encefalopatías/prevención & control , Carbamatos/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Fenilendiaminas/administración & dosificación , Sarín/toxicidad , Animales , Atropina/administración & dosificación , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encefalopatías/patología , Sustancias para la Guerra Química/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Masculino , Neuroglía/patología , Neuronas/patología , Canales de Potasio con Entrada de Voltaje/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/fisiología , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Trimedoxima/administración & dosificaciónRESUMEN
Objective: Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic, volatile warfare agent. Rats and guinea pigs exposed to sarin display cholinergic excitotoxicity which includes hyper-salivation, respiratory distress, tremors, seizures, and death. Here we focused on the characterization of the airways injury induced by direct exposure of the lungs to sarin vapor and compared it to that induced by the intramuscularly route. Materials and methods: Rats were exposed to sarin either in vapor (â¼1LCT50, 34.2 ± 0.8 µg/l/min, 10 min) or by i.m. (â¼1LD50, 80 µg/kg), and lung injury was evaluated by broncho-alveolar lavage (BAL). Results and discussion: BAL analysis revealed route-dependent effects in rats: vapor exposed animals showed elevation of inflammatory cytokines, protein, and neutrophil cells. These elevations were seen at 24 h and were still significantly higher compared to control values at 1 week following vapor exposure. These elevations were not detected in rats exposed to sarin i.m. Histological evaluation of the brains revealed typical changes following sarin poisoning independent of the route of administration. The airways damage following vapor exposure in rats was also compared to that induced in guinea pigs. The latter showed increased eosinophilia and histamine levels that constitutes an anaphylactic response not seen in rats. Conclusions: These data clearly point out the importance of using the appropriate route of administration in studying the deleterious effects of volatile nerve agents, as well as the selection of the appropriate animal species. Since airways form major target organs for the development of injury following inhalation toxicity, they should be included in any comprehensive evaluation of countermeasures efficacy.
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Sustancias para la Guerra Química/toxicidad , Pulmón/patología , Sarín/administración & dosificación , Sarín/toxicidad , Administración por Inhalación , Animales , Lavado Broncoalveolar , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/toxicidad , Cobayas , Inflamación , Inyecciones Intramusculares , Dosificación Letal Mediana , Pulmón/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
A common consequence of exposure to organophosphate nerve agents is the centrally mediated seizure activity that appears even after conventional treatment with atropine and oximes. We have previously demonstrated a major inflammatory response with subsequent brain damage which was correlated with the duration of the sarin-induced seizures (Chapman et al., 2006). In the present work seizures were induced by the nerve agent sarin (1.2 LD50) insufficiently treated 1 min later by atropine and trimedoxime bromide (TA), with additional midazolam treatment either 5 or 30 min after continuous seizure activity. The efficacy of both steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as other drugs that were reported as beneficial in neuroprotection, were evaluated for their contribution as adjunct treatment against sarin induced seizures and the ensuing inflammatory brain damage. Results show that both steroids and NSAIDs were harmful when administered during convulsions, and steroids were at best ineffective if administered at their termination. However, if administered at termination of convulsions, the NSAID ibuprofen, the selective COX 2 inhibitor nimesulide and the PLA2 inhibitor quinacrine were partially effective in reducing brain inflammatory markers. Administration of exogenous analogs of prostaglandins (PGE2) immediately following sarin-induced convulsions was found to have a beneficial effect in reducing brain inflammatory markers measured at 24 h and one week post sarin exposure. These findings support the hypothesis that elevated levels of PGE2 have a beneficial role immediately following sarin induced seizures, and that early inhibition of PGE2 production by both steroids and NSAID is contraindicative.
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Antiinflamatorios/uso terapéutico , Encefalopatías/inducido químicamente , Encefalopatías/prevención & control , Sustancias para la Guerra Química , Inhibidores de la Colinesterasa/toxicidad , Encefalitis/inducido químicamente , Encefalitis/prevención & control , Prostaglandinas/metabolismo , Sarín/toxicidad , Animales , Anticonvulsivantes/uso terapéutico , Atropina/uso terapéutico , Reactivadores de la Colinesterasa/uso terapéutico , Dinoprostona/metabolismo , Masculino , Midazolam/uso terapéutico , Agentes Nerviosos , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Trimedoxima/uso terapéuticoRESUMEN
OBJECTIVE: Posttraumatic stress disorder (PTSD) is frequently associated with depression and anxiety, but the nature of the relationship is unclear. By removing mood and anxiety diagnostic criteria, the 11th edition of the International Classification of Diseases (ICD-11) aims to delineate a distinct PTSD phenotype. We examined the effect of implementing ICD-11 criteria on rates of codiagnosed depression and anxiety in survivors with recent PTSD. METHOD: Participants were 1,061 survivors of traumatic injury admitted to acute care centers in Israel. ICD-10 and ICD-11 diagnostic rules were applied to the Clinician-Administered PTSD Scale for DSM-IV. Co-occurring disorders were identified using the Structured Clinical Interview for DSM-IV (SCID). Depression severity was measured by the Beck Depression Inventory-II (BDI-II). Assessments were performed 0-60 ("wave 1") and 90-240 ("wave 2") days after trauma exposure. RESULTS: Participants identified by ICD-11 PTSD criteria were equally or more likely than those identified by the ICD-10 alone to meet depression or anxiety disorder diagnostic criteria (for wave 1: depressive disorders, OR [odds ratio] = 1.98, 95% CI [confidence interval] = [1.36, 2.87]; anxiety disorders, OR = 1.04, 95% CI = [0.67, 1.64]; for wave 2: depressive disorders, OR = 1.70, 95% CI = [1.00, 2.91]; anxiety disorders, OR = 1.04, 95% CI = [0.54, 2.01]). ICD-11 PTSD was associated with higher BDI scores (M = 23.15 vs. 17.93, P < 0.001 for wave 1; M = 23.93 vs. 17.94, P < 0.001 for wave 2). PTSD symptom severity accounted for the higher levels of depression in ICD-11 PTSD. CONCLUSIONS: Despite excluding depression and anxiety symptom criteria, the ICD-11 identified equal or higher proportion of depression and anxiety disorders, suggesting that those are inherently associated with PTSD.
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Trastornos de Ansiedad/diagnóstico , Trastorno Depresivo/diagnóstico , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Clasificación Internacional de Enfermedades , Trastornos por Estrés Postraumático/diagnóstico , Adulto , Anciano , Ansiedad/complicaciones , Ansiedad/diagnóstico , Trastornos de Ansiedad/complicaciones , Depresión/complicaciones , Depresión/diagnóstico , Trastorno Depresivo/complicaciones , Diagnóstico Diferencial , Femenino , Humanos , Israel , Masculino , Persona de Mediana Edad , Trastornos por Estrés Postraumático/complicaciones , Sobrevivientes/psicologíaRESUMEN
Eye exposure to organophosphate (OP) irreversible acetylcholinesterase inhibitors, results in long-term miosis and impaired visual function. The aim of this study was to find an anticholinergic antidote, which would counteract miosis and visual impairment induced by the nerve agents sarin and VX with minimal untoward side-effects. Rat pupil width and light reflex were evaluated from 15 min up to 2 weeks following topical OP exposure with or without topical ocular treatment of atropine or homatropine or with a combined intramuscular treatment of trimedoxime (TMB-4) and atropine (TA). Visual function following insult and treatment was assessed using a cued Morris water maze task. Topical VX exposure showed a dose-dependent miosis with a significant reduction in visual function similar to the effect seen following sarin exposure. Homatropine (2%; w/v) and atropine (0.1%; w/v) treatment ameliorated both sarin and VX-induced miosis and the resulting visual impairment. TA treatment was sufficient in ameliorating the sarin-induced ocular impairment while an additional ocular treatment with either 0.1% atropine or 2% homatropine was necessary following VX exposure. To conclude the use of 0.1% atropine or 2% homatropine was beneficial in ameliorating the ocular insult following VX or sarin ocular exposure and thus should be considered as universal treatments against this intoxication. The findings also emphasize the necessity of additional ocular treatment to the systemic treatment in visually impaired casualties following VX exposure.
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Ojo/efectos de los fármacos , Agentes Nerviosos/toxicidad , Compuestos Organotiofosforados/toxicidad , Sarín/toxicidad , Animales , Antídotos/administración & dosificación , Atropina/administración & dosificación , Ojo/fisiopatología , Masculino , Miosis/tratamiento farmacológico , Pupila/efectos de los fármacos , Ratas , Ratas Long-Evans , Tropanos/administración & dosificación , Visión Ocular/efectos de los fármacosRESUMEN
Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic warfare agent. Following the overt, dose-dependent signs (e.g. tremor, hyper secretion, seizures, respiratory depression and eventually death), brain damage is often reported. The goal of the present study was to characterize the early histopathological and biochemical events leading to this damage. Rats were exposed to 1LD50 of sarin (80µg/kg, i.m.). Brains were removed at 1, 2, 6, 24 and 48h and processed for analysis. Results showed that TSPO (translocator protein) mRNA increased at 6h post exposure while TSPO receptor density increased only at 24h. In all brain regions tested, bax mRNA decreased 1h post exposure followed by an increase 24h later, with only minor increase in bcl2 mRNA. At this time point a decrease was seen in both anti-apoptotic protein Bcl2 and pro-apoptotic Bax, followed by a time and region specific increase in Bax. An immediate elevation in ERK1/2 activity with no change in JNK may indicate an endogenous "first response" mechanism used to attenuate the forthcoming apoptosis. The time dependent increase in the severity of brain damage included an early bi-phasic activation of astrocytes, a sharp decrease in intact neuronal cells, a time dependent reduction in MAP2 and up to 15% of apoptosis. Thus, neuronal death is mostly due to necrosis and severe astrocytosis. The data suggests that timing of possible treatments should be determined by early events following exposure. For example, the biphasic changes in astrocytes activity indicate a possible beneficial effects of delayed anti-inflammatory intervention.
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Encéfalo/efectos de los fármacos , Inhibidores de la Colinesterasa/toxicidad , Sarín/toxicidad , Animales , Sustancias para la Guerra Química , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The antidotal treatment of organophosphates (OP) nerve agents (NA) poisoning is based on anticholinergics (e.g. atropine) combined with oxime reactivators (e.g. 2PAM) of acetylcholinesterase (AChE). This treatment is symptomatic and does not degrade the OP. New small-molecule OP scavengers were developed as bifunctional hybrids. Their molecular design was based on combining a nucleophile that directly degrades OP with a moiety that reactivates OP-inhibited AChE. The OP degrading moiety is either benzhydroxamic acid (BHA) or 4-pyridinehydroxamic acid (4PHA) coupled via (CH2)n, (n = 1 or 3) to 2PAM. Three newly synthesized oxime-hydroxamate hybrids: 2PAMPr4PHA, 2PAMMeBHA and 2,4-DiPAMMeBHA were found to detoxify sarin, cyclosarin and soman in solution at 3-10-fold faster rate than 2PAM and to reactivate OP-AChE in vitro. 2PAMPr4PHA displayed 18-fold faster reactivation than 2-PAM of cyclosarin-inhibited HuAChE (kr = 3.6 × 102 vs. 0.2 × 102 M-1min-1, respectively, 37 °C). These hybrids inhibited AChE reversibly, IC50 = 16-48 µM, thereby decreasing the inhibition rates by OPs. The LD50 (im) of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA are >568, 508 and >506 µmol/kg in rats and 144, 203 and >506 µmol/kg in guinea pigs. The rate of blood ChE recovery by the hybrids administered either pre- or post-exposure to 0.8xLD50 sarin was comparable or faster than 2PAM. Antidotal efficacy of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA administered with atropine, as pre-treatment to sarin in rats (im), yielded protection ratios (PR) 11.6, 11.5 and 4.7, respectively, vs. 5.5 with 2PAM. Post-treatment against various OPs in rats and guinea-pigs yielded PRs higher or similar to that of 2 PAM. Our in vivo data indicates that some hybrids may serve as efficient small molecule scavengers for mitigating the toxicity of OP NAs.
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Agentes Nerviosos/toxicidad , Neurotoxinas/toxicidad , Bibliotecas de Moléculas Pequeñas/farmacología , Acetilcolinesterasa/sangre , Acetilcolinesterasa/metabolismo , Animales , Antídotos/farmacología , Inhibidores de la Colinesterasa/farmacología , Reactivadores de la Colinesterasa/farmacología , Cobayas , Humanos , Ácidos Hidroxámicos/química , Concentración 50 Inhibidora , Cinética , Masculino , Organofosfatos/toxicidad , Compuestos Organofosforados/toxicidad , Compuestos Organotiofosforados/toxicidad , Oximas/química , Fosforilación/efectos de los fármacos , Ratas Sprague-Dawley , Sarín/envenenamiento , Factores de Tiempo , Pruebas de Toxicidad AgudaRESUMEN
Rivastigmine, a reversible cholinesterase inhibitor, approved as a remedy in Alzheimer's disease, was suggested as pretreatment against nerve agents poisoning. We evaluated the pharmacokinetic, pharmacodynamic, physiologic, cognitive and emotional effects of repeated rivastigmine in young healthy male adults, in a double blind, placebo controlled crossover trial. Three groups completed 3 treatment periods: 0, 1.5 and 3mg twice a day, for a total of 5 intakes. Parameters monitored were: vital signs, ECG, laboratory tests, sialometry, visual accommodation, inspiratory peak flow, and cognitive function tests. Adverse reactions were mild. Peak blood levels and peak cholinesterase inhibition increased with repeated intakes, and high variability and non-linear pharmacokinetics were demonstrated. In addition, two cognitive functions were affected (perceptual speed and dynamic tracking). The complicated pharmacological profile and the high inter-personal variability limit the potential use of rivastigmine as pretreatment for war fighters and first responders.
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Cognición/efectos de los fármacos , Fármacos Neuroprotectores/sangre , Fármacos Neuroprotectores/farmacología , Rivastigmina/sangre , Rivastigmina/farmacología , Acetilcolinesterasa/metabolismo , Adolescente , Adulto , Estudios Cruzados , Método Doble Ciego , Emociones/efectos de los fármacos , Estudios de Seguimiento , Voluntarios Sanos , Humanos , Masculino , Saliva/metabolismo , Factores de Tiempo , Visión Ocular/efectos de los fármacos , Agudeza Visual/efectos de los fármacos , Adulto JovenRESUMEN
Sarin poisoned rats display a hyper-cholinergic activity including hypersalivation, tremors, seizures and death. Here we studied the time and dose effects of midazolam treatment following nerve agent exposure. Rats were exposed to sarin (1.2 LD50, 108 µg/kg, im), and treated 1 min later with TMB4 and atropine (TA 7.5 and 5 mg/kg, im, respectively). Midazolam was injected either at 1 min (1 mg/kg, im), or 1 h later (1 or 5 mg/kg i.m.). Cortical seizures were monitored by electrocorticogram (ECoG). At 5 weeks, rats were assessed in a water maze task, and then their brains were extracted for biochemical analysis and histological evaluation. Results revealed a time and dose dependent effects of midazolam treatment. Rats treated with TA only displayed acute signs of sarin intoxication, 29% died within 24h and the ECoG showed seizures for several hours. Animals that received midazolam within 1 min survived with only minor clinical signs but with no biochemical, behavioral, or histological sequel. Animals that lived to receive midazolam at 1h (87%) survived and the effects of the delayed administration were dose dependent. Midazolam 5 mg/kg significantly counteracted the acute signs of intoxication and the impaired behavioral performance, attenuated some of the inflammatory response with no effect on morphological damage. Midazolam 1mg/kg showed only a slight tendency to modulate the cognitive function. In addition, the delayed administration of both midazolam doses significantly attenuated ECoG compared to TA treatment only. These results suggest that following prolonged seizure, high dose midazolam is beneficial in counteracting adverse effects of sarin poisoning.
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Lesiones Encefálicas/inducido químicamente , Lesiones Encefálicas/tratamiento farmacológico , Inhibidores de la Colinesterasa/toxicidad , Hipnóticos y Sedantes/administración & dosificación , Midazolam/administración & dosificación , Sarín/toxicidad , Análisis de Varianza , Animales , Lesiones Encefálicas/fisiopatología , Proteínas Portadoras/metabolismo , Citocinas/metabolismo , Dinoprostona/metabolismo , Esquema de Medicación , Electroencefalografía , Ensayo de Inmunoadsorción Enzimática , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/metabolismo , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
OBJECTIVE: Exposure to organophosphates (OP) may lead to a life threatening cholinergic crisis with death attributed to a rapidly progressive respiratory failure. In a toxicological mass casualty event involving organophosphate exposure, many of the victims may depend on immediate short-term ventilation to overcome the respiratory distress which may exhaust life supporting resources. In addition, the mandatory use of personal protective gear by first responders emphasizes the need for a noninvasive, easy-to-operate ventilation device. Our objective was to assess the efficacy of MRTX, a Biphasic Cuirass Ventilation device, in comparison with standard bag-valve mask ventilation following acute organophosphate poisoning. METHODS: Pigs were exposed to paraoxon poisoning (1.4 LD50), and treated 8 min later with atropine (0.05 mg/kg). The control group received no further support (n = 9), the two experimental groups received ventilation support initiated 15 min post exposure and lasted for 25 min: one group was ventilated with the commonly used bag-valve mask (Mask group, n = 7) and the other was ventilated with the Biphasic Cuirass Ventilation device (Cuirass group, n = 7). Clinical signs and physiological parameters were monitored during the first hour, and mortality up to 24 h post exposure was recorded. RESULTS: No mortality was observed in the Cuirass group following OP poisoning, while mortality in the Control and in the Mask groups was high (67% and 71%, respectively). Mouth excretions of the cuirass-ventilated animals were frothy white as in deep suctioning, as opposed to the clear saliva-like appearance of secretions in the other two groups. No further group differences were recorded. CONCLUSIONS: The noninvasive, easy-to-operate Biphasic Cuirass Ventilation device was effective in reducing OP-induced mortality and might be advantageous in an organophosphate mass casualty event. This finding should be validated in further investigations.
RESUMEN
Sarin, a potent organophosphate cholinesterase inhibitor, induces an array of toxic effects including convulsions. Many antidotal treatments contain anticonvulsants to block seizure activity and the ensuing brain damage. Magnesium sulfate (MGS) is used to suppress eclamptic seizures in pregnant women with hypertension and was shown to block kainate-induced convulsions. Magnesium sulfate was evaluated herein as an anticonvulsant against sarin poisoning and its efficacy was compared with the potent anticonvulsants midazolam (MDZ) and caramiphen (CRM). Rats were exposed to a convulsant dose of sarin (96 µg/kg, im) and 1 min later treated with the oxime TMB4 and atropine to increase survival. Five minutes after initiation of convulsions, MGS, CRM, or MDZ were administered. Attenuation of tonic-clonic convulsions was observed following all these treatments. However, radio-telemetric electro-corticography (ECoG) monitoring demonstrated sustained seizure activity in MGS-injected animals while this activity was completely blocked by MDZ and CRM. This disrupted brain activity was associated with marked increase in brain translocator protein levels, a marker for brain damage, measured 1 week following exposure. Additionally, histopathological analyses of MGS-treated group showed typical sarin-induced brain injury excluding the hippocampus that was partially protected. Our results clearly show that MGS demonstrated misleading features as an anticonvulsant against sarin-induced seizures. This stems from the dissociation observed between overt convulsions and seizure activity. Thus, the presence or absence of motor convulsions may be an unreliable indicator in the assessment of clinical status and in directing adequate antidotal treatments following exposure to nerve agents in battle field or terror attacks.
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Anticonvulsivantes/farmacología , Antídotos/farmacología , Sustancias para la Guerra Química/envenenamiento , Sulfato de Magnesio/farmacología , Sarín/envenenamiento , Convulsiones/tratamiento farmacológico , Animales , Lesiones Encefálicas/inducido químicamente , Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Ciclopentanos/farmacología , Epilepsia Tónico-Clónica , Masculino , Midazolam/farmacología , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Convulsiones/fisiopatología , TelemetríaRESUMEN
Highly emotional, stress reactive BALB/c mice secrete more corticosterone in response to fear conditioning than the low stress reactive C57BL/6J mice. Fear memory to cue and context differs between the strains. We injected corticosterone at physiological concentrations (250 µg/kg i.p.) 30 min before fear conditioning. Fear memory was tested 48 and 72 h later. Although corticosterone had little effect on acquisition, it differentially affected fear memories in strain dependent manner: while BALB/c mice decreased freezing during cue and context episodes, C57BL/6J mice showed an overall increase in freezing. BALB/c mice showed extinction over days while no such extinction was seen in C57BL/6J mice. Evaluation of these data in the perspective of previous studies using the same fear conditioning paradigm with corticosterone injections 5 min before or immediately after acquisition, revealed the impact of corticosterone during conditioning on the strength of fear memories. In C57BL/6J mice the overall increase in fear memories was higher if corticosterone was injected 30 min pre acquisition than if injected 5 min pre. In contrast, BALB/c mice showed reduced fear memories when injected 30 min pre compared to that seen 5 min pre acquisition. Both strains showed decreased fear memories compared to vehicle if corticosterone was administered immediately after acquisition. We conclude that the timing of physiologically relevant, stress levels increase in corticosterone is essential for the processing of aversive events and the formation of fear memories. However, the quality of the effect depends on the genetic background. These findings contribute to the understanding of the etiology of stress-related disorders.
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Corticosterona/farmacología , Señales (Psicología) , Miedo/efectos de los fármacos , Memoria/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Emociones/efectos de los fármacos , Reacción Cataléptica de Congelación/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Especificidad de la Especie , Factores de TiempoRESUMEN
The highly toxic organophosphorous compound VX [O-ethyl-S-(isoporopylaminoethyl) methyl phosphonothiolate] undergoes an incomplete decontamination by conventional chemicals and thus evaporates from urban surfaces, e.g., pavement, long after the initial insult. As a consequence to these characteristics of VX, even the expected low levels should be examined for their potential to induce functional impairments including those associated with neuronal changes. In the present study, we developed an animal model for subchronic, low-dose VX exposure and evaluated its effects in rats. Animals were exposed to VX (2.25 microg/kg/day, 0.05 LD(50)) for three months via implanted mini osmotic pumps. The rapidly attained continuous and marked whole-blood cholinesterase inhibition (approximately 60%), fully recovered 96 h post pump removal. Under these conditions, body weight, blood count and chemistry, water maze acquisition task, sensitivity to the muscarinic agonist oxotremorine, peripheral benzodiazepine receptors density and brain morphology as demonstrated by routine histopathology, remained unchanged. However, animals treated with VX showed abnormal initial response in an Open Field test and a reduction (approximately 30%) in the expression of the exocytotic synaptobrevin/vesicle associate membrane protein (VAMP) in hippocampal neurons. These changes could not be detected one month following termination of exposure. Our findings indicate that following a subchronic, low-level exposure to the chemical warfare agent VX some important processes might be considerably impaired. Further research should be addressed towards better understanding of its potential health ramifications and in search of optimal countermeasures.
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Química Encefálica/efectos de los fármacos , Sustancias para la Guerra Química/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/psicología , Compuestos Organotiofosforados/toxicidad , Animales , Conducta Animal/efectos de los fármacos , Recuento de Células Sanguíneas , Análisis Químico de la Sangre , Western Blotting , Peso Corporal/efectos de los fármacos , Encéfalo/patología , Inhibidores de la Colinesterasa/administración & dosificación , Colinesterasas/sangre , Colinesterasas/metabolismo , Enfermedad Crónica , Implantes de Medicamentos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Agonistas Muscarínicos/farmacología , Síndromes de Neurotoxicidad/fisiopatología , Compuestos Organotiofosforados/administración & dosificación , Oxotremorina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/efectos de los fármacos , Fracciones Subcelulares/efectos de los fármacos , Fracciones Subcelulares/enzimologíaRESUMEN
Freely moving rats were exposed to sarin vapor (34.2+/-0.8 microg/l) for 10 min. Mortality at 24 h was 35% and toxic sings in the surviving rats ranged from sever (prolonged convulsions) through moderate to almost no overt signs. Some of the surviving rats developed delayed, intermittent convulsions. All rats were evaluated for long-term functional deficits in comparison to air-exposed control rats. Histological analysis revealed typical cell loss at 1 week post inhalation exposure. Neuronal inflammation was demonstrated by a 20-fold increase in prostaglandin (PGE(2)) levels 24 h following exposure that markedly decreased 6 days later. An additional, delayed increase in PGE(2) was detected at 1 month and continued to increase for up to 6 months post exposure. Glial activation following neural damage was demonstrated by an elevated level of peripheral benzodiazepine receptors (PBR) seen in the brain 4 and 6 months after exposure. At the same time muscarinic receptors were unaffected. Six weeks, four and six months post exposure behavioral evaluations were performed. In the open field, sarin-exposed rats showed a significant increase in overall activity with no habituation over days. In a working memory paradigm in the water maze, these same rats showed impaired working and reference memory processes with no recovery. Our data suggest long lasting impairment of brain functions in surviving rats following a single sarin exposure. Animals that seem to fully recover from the exposure, and even animals that initially show no toxicity signs, developed some adverse neural changes with time.
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Sustancias para la Guerra Química/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Neuronas/patología , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/psicología , Sarín/toxicidad , Administración por Inhalación , Animales , Encéfalo/patología , Química Encefálica/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/análisis , Cognición/efectos de los fármacos , Dinoprostona/metabolismo , Gases , Dosificación Letal Mediana , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Receptores Muscarínicos/efectos de los fármacos , Receptores Muscarínicos/metabolismo , Sarín/administración & dosificación , Sarín/análisisRESUMEN
BACKGROUND: It has been well accepted that glial cells in the central nervous system (CNS) produce nitric oxide (NO) through the induction of a nitric oxide synthase isoform (NOS2) only in response to various insults. Recently we described rapid astroglial, NOS2-dependent, NO production in the neocortex of healthy mice on a time scale relevant to neuronal activity. To explore a possible role for astroglial NOS2 in normal brain function we investigated a NOS2 knockout mouse (B6;129P2-Nos2(tm1Lau)/J, Jackson Laboratory). Previous studies of this mouse strain revealed mainly altered immune responses, but no compensatory pathways and no CNS abnormalities have been reported. METHODOLOGY/PRINCIPAL FINDINGS: To our surprise, using NO imaging in brain slices in combination with biochemical methods we uncovered robust NO production by neocortical astrocytes of the NOS2 mutant. These findings indicate the existence of an alternative pathway that increases basal NOS activity. In addition, the astroglial mutation instigated modifications of neuronal attributes, shown by changes in the membrane properties of pyramidal neurons, and revealed in distinct behavioral abnormalities characterized by an increase in stress-related parameters. CONCLUSIONS/SIGNIFICANCE: The results strongly indicate the involvement of astrocytic-derived NO in modifying the activity of neuronal networks. In addition, the findings corroborate data linking NO signaling with stress-related behavior, and highlight the potential use of this genetic model for studies of stress-susceptibility. Lastly, our results beg re-examination of previous studies that used this mouse strain to examine the pathophysiology of brain insults, assuming lack of astrocytic nitrosative reaction.
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Astrocitos/metabolismo , Neocórtex/metabolismo , Neuronas/metabolismo , Óxido Nítrico Sintasa de Tipo II/fisiología , Óxido Nítrico/biosíntesis , Animales , Conducta Animal , Western Blotting , Calcio/metabolismo , Ratones , Ratones Mutantes , Neocórtex/citología , Óxido Nítrico Sintasa de Tipo II/genética , FenotipoRESUMEN
SUMMARY: ABSTRACT It has been well established that patients with schizophrenia have impaired cognitive abilities on neuropsychological tasks related to memory. Previous studies also suggest a central role for serotonin in memory. This double-blind crossover study aimed to explore the effect of l-tryptophan, a serotonin precursor, on a variety of memory tasks in schizophrenic patients. Antipsychotic-treated schizophrenic patients in remission (N = 21) were randomly treated with l-tryptophan or placebo and then evaluated at three consecutive points on clinical measures (including Positive and Negative Syndrome Scale for Schizophrenia, Clinical Global Impression, and Extrapyramidal Symptoms Rating Scale) and by neuropsychological tests (including Digit-Span, Paired Association, Rey-Osterich Complex Figure Test, Digit Symbol, Number Facility Test, and the Rivermead Behavioral Memory Tests. Compared with placebo, l-tryptophan had a beneficial effect on memory functions but not on the patients' psychotic state or on the side effects of medications. These preliminary results suggest the possibility of using serotonin precursor to enhance memory function in schizophrenia.
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Memoria/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Triptófano/farmacología , Adulto , Antipsicóticos/uso terapéutico , Estudios Cruzados , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Masculino , Trastornos de la Memoria/diagnóstico , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/psicología , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Esquizofrenia/diagnóstico , Triptófano/uso terapéuticoRESUMEN
BACKGROUND: The aim of this study was to compare the biochemical and physiological responses of fast vs. slow rewarming from moderate hypothermia in anaesthetized rats. METHODS: Anaesthetized rats were surface cooled to 28 degrees C, for 20 min, then rewarmed either quickly over 30 min or slowly over 120 min with monitoring of vital signs, systemic vascular resistance (SVR), cardiac output, biochemical changes and activity for 31 days. RESULTS: At hypothermia, cardiac output decreased to 77 +/- 38 ml x min(-1) and lactate increased to 4.62 +/- 4.73 mmol x l(-)1. Fast rewarming caused an abrupt increase in cardiac output (270 +/- 24 ml x min(-1)) and a sharp drop in SVR (325.6 +/- 23.3 dyne x s(-1) x cm(-5)), compared with a smoother course with cardiac output (142 +/- 18 ml x min(-1), P < 0.01) and SVR (662.8 +/- 41.0 dyne x s(-1) x cm(-5), P < 0.01), measured during slow rewarming. Lactate failed to return to normal values (upon returning to normothermia) (2.5 +/- 0.75 mmol x l(-1)) only in the fast rewarming group. In both groups, activity in the open field was not different from control rats. CONCLUSIONS: In rats, moderate hypothermia for 20 min does not appear to cause lasting biochemical or behavioural consequences, whether rewarming lasted over 30 or 120 min. However, there was a greater early change in cardiac output and heart rate, due to systemic vasodilatation in the fast rewarming animals. These acute changes may have consequences in patients with compromised cardiovascular reserves.